The concept of the topical microbicide is attractive - a safe and effective, female-controlled product destined for intravaginal use and intended to protect women from acquiring sexually transmitted diseases (STDs). With an increasing number of compounds identified as potential microbicides it is important to develop strategies for identifying the most promising candidates. Studies in Projects 1 and 2 and Core B will identify compounds with excellent in vitro antimicrobial activity against important STD pathogens and outstanding safety profiles. In this project we will investigate the efficacy and safety of selected candidate microbicides using well-characterized animal model of genital tract infection. In specific aim 1 we will use mouse and guinea pig models of herpes simplex virus (HSV) and chlamydial genital tract infection to assess the ability of microbicides to limit cervico-vaginal infection and, in the case of the genital herpes models, prevent disease. Using these models we will also explore whether microbicides can prevent spread of the pathogen to important secondary sites: for HSV, to sensory ganglion neurons; and for chlamydia, to the upper genital tract. These models allow us explore the effectiveness of promising compounds for either pre- or post-coital use. In specific aim 2 we will use animal models to examine how microbicides efficacy can be affected by the presence of body fluids (e.g. blood or semen). We will explore whether microbicides might reduce STD transmission from infected women to susceptible male partners by determining whether microbicides can reduce the amount of organism present in cervico-vaginal secretions and by developing and using new murine models of STD transmission. In specific aim 3 we will explore the important safety issue of whether microbicides are immunotoxic. Using standard immunological methods to assess genital tract immunity, we will explore the potential of candidate microbicides to impact innate immune responses known to be important in protecting the female genital tract against infection by sexually transmitted pathogens. These studies will provide important information regarding the in vivo effectiveness of candidate microbicides in protecting female animals against two important STD pathogens. These experiments will also explore the issue of whether microbicides can impact female to male STD transmission and investigate the important question of whether microbicides are immunotoxic to the female genital tract. Collectively, theses studies will characterize the in vivo behavior of microbicides and identify compounds with outstanding efficacy and safety profiles. Overall, this research is expected to yield information that will allow for the rational prioritization of microbicides for further evaluation in clinical trials.